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Integrin Activation as a Treatment for Leukocyte Adhesion Deficiencies

Award Number: R41AI145507
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/08/2019
PERIOD OF PERFORMANCE END DATE: 02/28/2021

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Integrin Activation as a Treatment for Leukocyte Adhesion Deficiencies - Leukocyte adhesion deficiency type I (LAD1) is a rare and often fatal primary immunodeficiency. It is caused by autosomal recessive mutations in the gene ITGB2, which encodes CD18 (the common ß2 subunit) of the ß2 family of integrin cell adhesion molecules that are specifically expressed on cells of hematopoietic origin like leukocytes. As a result of decreased function of ß2 integrins, leukocytes cannot extravasate from the vasculature and patients suffer from severe life threatening and recurrent non-pustular infections of the soft tissue including skin, mucosal membranes, and intestinal track. Hematopoietic stem cell transplantation is curative, but it is not without significant risk. In more moderate forms of the disease, integrin ß2 expression is characterized as being between 2 – 30% of normal levels. An intriguing approach to overcoming the adhesion defects found in moderate LAD1 patients would be to directly activate ß2 integrins, like aLß2, so that even low levels of this integrin would be sufficient to support essential leukocyte functions. Scientists at the Texas Heart Institute have developed a library of small molecule compounds that can directly bind and activate integrin cell adhesion receptors including the integrin aLß2. These compounds are currently licensed to 7 Hills Pharma and are being developed for immuno-oncology (IO) indications as they can stimulate the immune system and synergize with checkpoint blockade therapies like anti-CTLA-4 and anti-PD(L)1. However, there is a clear opportunity to leverage these compounds as a treatment strategy to activate integrins like aLß2 and directly target the cause of LAD1. In this phase I SBIR proposal, we will test the hypothesis that activation of ß2 integrins with small molecule compounds can overcome the adhesion defects seen in leukocytes of LAD1 patients, and in an animal model of moderate LAD1. In proposed aims we will screen over 500 integrin activating compounds, from 5 structural classes, to identify potent ß2 integrin activators. Representative compounds from each structural class will then be tested against a panel of mutations identified from moderate LAD1 patients. In vivo proof-of-concept experiments will be performed by testing integrin activating compounds in acute inflammatory responses in the CD18hypo mouse, which mimics moderate LAD1. Lastly, pharmacodynamic models of compound activity will be developed to inform future clinical development. The goal of this drug development program is the development of a safe and effective orally available treatment for patients with moderate to severe LAD1, an orphan disease indication for which there are no effective treatments outside of bone-marrow transplantation.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	7 HILLS PHARMA LLC	2126 SHERIDAN ST	HOUSTON	TX	77030	HARRIS	USA	Allergy and Infectious Diseases Research	000	1	6/15/2021	NEW	$0
														Subtotal = $0

Issue Date FY: 2019 ( Subtotal = $243,282 )
2019	2019	7 HILLS PHARMA LLC	8285 EL RIO STE 130	HOUSTON	TX	77054	HARRIS	USA	Allergy and Infectious Diseases Research	000	1	3/7/2019	NEW	$243,282
														Subtotal = $243,282

Grand Total All Awards = $243,282

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Integrin Activation as a Treatment for Leukocyte Adhesion Deficiencies

Award Number: R41AI145507

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/08/2019

PERIOD OF PERFORMANCE END DATE: 02/28/2021

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